Frailty is a physiological syndrome characterized by decreased reserve and diminished resistance to stressors. Frailty has been shown to be more common among individuals with chronic kidney disease (CKD) than among those with normal kidney function.1 In addition, frailty has been demonstrated to predict mortality and morbidity.2 However, several important aspects of the relationship between frailty and CKD remain unclear. First, has the use of estimates of GFR based on serum creatinine led to underestimation of the association between frailty and CKD, given that sarcopenia is an important part of frailty? Second, is the association between frailty and CKD actually bidirectional? Third, is the mechanism central to the association driven by an acceleration of chronic inflammation? To date, most work has focused on the hypothesis that CKD leads to frailty, but it is entirely possible that frailty may in turn be associated with worse kidney outcomes, such as more rapid progression of kidney disease. Fourth, can frailty be addressed in CKD patients? Interventions to address frailty have the potential to lead to better outcomes, including slowed progression of CKD and physical dysfunction as well as ultimately better survival, but this possibility has not yet been explored. My long-term goal is to become an independent investigator in the area of the overlap between CKD and physical functioning. The overall objective of this application is to lay the foundations to gain expertise n the relationship and underlying mechanism of frailty with chronic kidney disease. The central hypotheses are that frailty is associated with CKD and its progression and that frailty can be addressed to improve functioning and outcomes among patients with moderate to severe CKD. This proposal will use existing data from two large NIDDK cohorts, Modification of Diet in Renal Disease study (MDRD) and the African American Study of Kidney Disease and Hypertension (AASK), as well as primary data collection to address these hypotheses. This combination of a variety of study methods and a strong mentoring team will simultaneously advance my long-term goal. The healthcare system supported by the department of veterans' affairs services approximately 22,658,145 veterans in 2010, of which 545,763 are over the age of 65. Medical care expenditure has demonstrated a steady rise in cost since 1971. The clinical syndrome of frailty has been independently associated to increased number of hospitalizations and falls in the general population which undoubtedly has lead to a rise in the use of health care dollars. By addressing the above clinical questions, secondary prevention of the syndrome may be achieved to lower the number of hospitalizations. The above objectives are in line with major initiatives of the VA Strategic Plan FY 2010-2014, through the strategic goal of improving the quality of health care as well as increasing veteran client satisfaction with health and counseling. The veteran chronic kidney disease client will maximally benefit from the future clinical implementation resultant from the proposed work by improving quality of life measures in the identification and intervention of those who are frail. In addition the above proposal offers a opportunity for improvements in communication across specialties in a collaborative effort to improve the lives of veterans. PUBLIC HEALTH RELEVANCE: Frailty is a syndrome characterized by decreased reserve and diminished resistance to stressors. The proposed research will evaluate the association of frailty with chronic kidney disease (CKD). The prevalence of frailty increases with age and with CKD, but studies are needed to determine whether frailty is associated with worsening of CKD and whether intervention to treat frailty can improve physical functioning and health- related quality of life (HRQOL) as well as slow the progression of CKD. Veterans Health Administration serves many elderly patients who are particularly likely to have CKD and to be frail. Addressing frailty could lead to a reduction in hospitalizations and falls as well as prolongation of the time to ESRD, in line with the major initiative of the VA Strategic Plan FY 2010-2014 to improve the quality of health care and increase veteran satisfaction with health and counseling.